The present invention relates especially to chimeric polypeptides composed of a biologically active portion consisting of all or part of G-CSF or of a variant of G-CSF, and an essentially proteinaceous stabilizing structure endowing it with new biological properties.
Human G-CSF is a secreted polypeptide of 174 amino acids having a molecular weight of approximately 18 kD. It was isolated initially from a cancer cell line (EP 169,566), and its gene has been cloned, sequenced and expressed in different cell hosts by genetic engineering techniques (EP 215,126, EP 220,520). An mRNA potentially coding for a form of G-CSF having 177 amino adds has, moreover, been detected [Nagata S. et al., EMBO J. 5 (1986) 575-581]. G-CSF possesses the capacity to stimulate the differentiation and proliferation of bone marrow stem cells to granulocytes. As such, it possesses the capacity to stimulate the body's protective capacities against infection by promoting the growth of polymorphonuclear neutrophils and their differentiation ending in maturity. It is thus capable of activating the body's prophylactic functions, and may be used in different pathological situations in which the number of neutrophils is abnormally low or in which the immune system needs to be strengthened. Such situations arise, for example, following cancer chemotherapy treatments, in transplantation, and especially bone marrow transplantation, or in leukopenic states.
One of the drawbacks of currently available G-CSF lies in the fact that it is rapidly degraded by the body once administered. This is all the more noticeable for the fact that G-CSF is generally used at low doses. Furthermore, the use of larger doses has not been able to permit therapeutic capacities of this molecule to be improved, and may induce adverse side effects. These phenomena of elimination and degradation in vivo hence constitute at present an obstacle to exploitation of the biological activity of the G-CSF as a pharmaceutical agent.